Antimicrobial locking solutions comprising taurinamide derivatives and biologically acceptable salts and acids, with the addition of small concentrations of heparin

ABSTRACT

The present invention relates to inhibiting or preventing infection and protecting against patency complications after a blood catheter has been inserted in a patient comprising administering to the device a pharmaceutically effective amount of a composition comprising:
         (A) at least one taurinamide derivative,   (B) at least one compound selected from the group consisting of biologically acceptable acids and biologically acceptable salts thereof; and   (C) heparin at a low concentration.

FIELD OF THE INVENTION

The present invention relates to an improved composition for preventinginfection and clotting in hemodialysis catheters. The invention furtherrelates to an improved composition for maintaining patency of indwellingcatheters involved in central blood access.

BACKGROUND OF THE INVENTION

Hemodialysis access systems for access to a patient's vascular systemfor exchange of blood between the vascular system and an externalprocessing apparatus are well known in the art. The simplest such systemis a catheter alone placed directly in the patient's right jugular veinwith the distal end extending into the central venous system, typicallyinto the superior vena cava. Other more complicated systems, for exampleports, usually involve indwelling catheters as well. The exchange ofblood for hemodialysis treatment typically involves high blood flowrates under conditions designed not to induce shear stress beyond acertain level so as to not cause red cell damage or the activation ofplatelets.

As with any implanted device, placement of an object that must remain inthe patient over a protracted period of time gives rise to thelikelihood of blood stream infection promoted by the indwelling device.Infection risk is seriously aggravated by the fact that such devices arefrequently handled and manipulated by medical workers, leading tomicrobial colonization of the catheter's internal surfaces, that is,formation of a biofilm in the lumen. Infection from a biofilm reservoiris much more serious than a simple infection, since it is oftenimpossible to eradicate with conventional means. In refractory cases thedevice must be explanted to treat the patient effectively. As a result,the literature, both scientific and patent, is replete with hopeful butnot definitive suggestions as to how to defeat, or at least hold at bay,catheter related infections.

In describing approaches to preventing or treating catheter infections,authors and practitioners generally refer to “locking” the catheter, butalso sometimes use the term “flushing” the catheter. Usage in the caseof the term “flushing” is ambiguous, and therefore some explanation ofterminology is necessary. With respect to implanted catheters, authorsand practitioners typically speak of “locking” a catheter between uses.In this context, “locking” means filling the catheter lumen with asubstance that is biocidal or an anticoagulant but preferably both.followed by leaving it there until the catheter has to be used again.(Typically, “locking” a catheter with a given solution also includes inthe assumed procedure the follow up event of withdrawing the solutionfrom the catheter before using, for example, a syringe to suck thesolution out of the catheter whenever the catheter must be used again.)For example. in the past authors or practitioners have spoken of heparinas a catheter lock. That word usage is relatively unambiguous.

Authors and practitioners have. however. not used the terms “flush” and“flushing” unambiguously. Much of the time “flushing” has a meaning thatis familiar to non-experts, namely sending a fluid through the catheteror into it and quickly back out again as a kind of washing. However. asubstantial fraction of authors and practitioners also use the terms“flush” and “flushing” as synonymous with “lock” and “locking” asdefined above. that is, meaning putting a solution in a catheter andleaving it there for an extended period and then taking it out when thepractitioner wants to use infuse the patient or remove fluid from thepatient. In this application the former meaning of “flush” and“flushing” is generally intended. However, in reviewing the literaturethe other usage must be borne in mind.

Antibiotics have been used to treat devices such as catheters to preventinfection, but chronic use of antibiotics as a prophylactic acceleratesemergence of antibiotic-resistant bacterial strains. Advances incatheter locks described in the scientific literature and other patentdocuments have involved the use of a substance generally referred to astaurolidine and/or taurinamide and taurinamide derivatives for routineantimicrobial use, in particular in catheters. Taurolidine and relatedcompounds are biocidal but are known not to induce development ofresistant bacterial strains. For example, Sodemann, U.S. Pat. No.6,166,007, issued Dec. 26, 2000 and Sodemann, U.S. Pat. No. 6,423,706,issued Jul. 23, 2002, among others, disclosed use of taurolidine andother taurinamide-related compounds as part of a catheter lock solution.

Coagulation of the blood inside catheters in or connected to thevascular system has also proven troublesome and many methods have beentried for its prevention, particularly for inhibiting the clogging ofthe catheter, which can diminish or destroy the catheter's usefulness.It is standard procedure to flush blood from the catheters and then lockthem with a heavy-duty anticoagulant, heparin locking solution being thestandard. Unfortunately heparin alone lacks biocidal capability, butthis deficiency is often ignored.

Current indwelling blood catheter maintenance practices, particularlywith respect to hemodialysis catheters, have evolved to the point wherecurrent de facto practices require that an extremely high concentrationheparin be instilled as a lock between uses. Normally the heparin lockconcentration is 5,000 units per ml. By comparison, therapeutic levelsin the blood to prevent clotting in patients with disorders wherebytheir blood to form clots are generally in the range of 0.2 to 0.4 unitsper ml. It is also known that blood used in laboratory experiments canbe maintained in a fluid state (i.e., not clotted) by using a heparinconcentration in the range of 5 units or so.

Unfortunately, and contrary to good catheter locking practice, sometimesmedical personnel flush heparin—in the flow-through sense—from thecatheter directly into the patient instead of drawing it out, e.g., witha syringe. Such events may be accidental or even in some casesdeliberate when the practitioner is attempting to unblock a clottedcatheter. An important consideration in the use of heparin is that iftoo much heparin is pushed into the patient's vascular system thepatient may become systemically anticoagulated, creating a significantrisk to the patient bleeding out. that is. dying of uncontrollablehemorrhage. Further, sonic patients are allergic to heparin. For bothreasons. minimizing systemic administration of heparin is important.

U.S. Pat. Nos. 6,166,007 and 6,423,306, cited above, disclosed solutionsbased on taurinamide derivatives. preferably taurolidine, combined withbiologically benign salts and corresponding acids. most preferablycitrate salts along with citric acid, as catheter locking solutions andsolutions for maintaining implants having both antimicrobial andanticoagulant properties. Selection of optimum concentrations of thesesubstances while also controlling the pH of the solution to be generallyslightly acidic increases the antimicrobial efficacy of taurolidine insolution.

Other substances could be used as anticoagulants, for example EDTA,enoxaparin sodium, coumarin, indanedione derivative, anisindione,warfarin, protamine sulfate, streptokinase, urokinase, and others.However, the properties of citrate and citric acid in a proper pHbalance give special effectiveness to catheter locks of the referencedformulation.

It has been empirically found in practicing the above-referencedpatents, however, that sometimes taurolidine reacts with a patient's redblood cells inside the catheter and changes the characteristics of theblood clot that normally forms at the distal end of the catheter. Thischange sometimes results in clot fragments or nuclei remaining attachedto the interior luminal surface of the catheter after the lock solutionis withdrawn in preparation for catheter use. The end result of even asmall clot fragment attached to the inside of a catheter is at leastpartial obstruction of flow through the catheter. In the case ofhemodialysis catheters, this causes a significant increase in resistanceto blood flow in the catheter. Too high a resistance increase may causeblood damage and can also reach an upper limit that requires a reductionin blood flow rate. Such flow resistance interferes with dialysisefficiency and extends dialysis time of treatment.

The formulation of taurolidine with citrate and citric acid described inU.S. Pat. Nos. 6,166,007 and 6,423,706, cited above, has worked well inminimizing catheter-caused infections in hemodialysis patients Dr.Sodemann, conducted initial trials of these compositions includingevaluation of pH values for maximizing the antimicrobial properties ofthe composition.

Dr. Sodemann and others also performed clinical trials of the finalcompositions in Europe to obtain approval for commercialization there.The data from Europe demonstrated nearly complete elimination ofcatheter related bloodstream infection, compared to the rate observedwith heparin locks and simultaneous achievement of a catheter patencyrate (the inverse of the rate of complications due to blood flowresistance during hemodialysis) comparable to that of heparin locksolutions.

Subsequently, in 2001 and 2002, however, the University of AlabamaMedical Center conducted a hemodialysis clinical trial using theSodemann taurolidine lock formulation. The clinical results confirmedthe low infection rate with the taurolidine based lock solution.However, this trial experienced a high rate of catheter patencycomplications compared with the heparin lock control group. Allon, M.,“Prophylaxis against dialysis catheter-related bacteremia with a novelantimicrobial lock solution,” Clinical Infec. Dis. 2003 (June) 15; 36(12): 1539-44.

The usual intervention to correct observed high flow resistance in ahemodialysis catheter is a clot-lysing procedure, which cleans out thecatheter. Whenever the University of Alabama practitioners experienced apatency complication. they would perform the clot lysing procedure,which was rapid and 100% successful. This result suggested that the flowresistance was caused by internal adhesion to the catheter. Thecalculation of catheter patency complication intervention in theUniversity of Alabama study was determined by taking the number oflysing procedures performed during the study period and dividing it bythe sum of patient days in the trial. The patency complication rate forthe group receiving the taurolidine-based locking solution wasapproximately 4 times higher than for the heparin lock group.

In hemodialysis, blood is withdrawn from the patient via a catheterlumen with its tip in a major blood supply. The blood enters a machinewhich removes toxins and water from the blood. In U.S. hemodialysispractice, unlike European practice, the blood flow rate is higher andtypically approximately 400 ml/min. In order not to damage blood cellsat this flow rate, practitioners monitor the flow resistance in thecatheter and if the resistance increases above an alarm setting theoperator must clear the catheter or slow down the flow. (Lower flow rateis necessary in such situations because the combination of high flowrates and obstructions creates eddies and other non-laminar flowconditions that create shear forces that damage blood cells.) However,slower flow rates require a considerable increase in the time ofdialysis to achieve the same level of toxin removal, lengthening thetime necessary for an effective hemodialysis session. Longer sessionslower both patient acceptance and clinic productivity.

Several differences in medical practice between the European trials andthe U.S. trials probably contributed to the difference in result.Especially significant was that higher blood flow rates are set duringdialysis in the U.S. and a different catheter was used in the U.S.clinical trials.

In addition, careful observation taught that, after instillation of alock solution into a catheter, a small amount of lock solution flows outof the catheter into the patient's vascular system. The lost catheterlock is replaced by blood in the distal tip region of the catheter. Thisphenomenon is described by Polaschegg, published U.S. Patent ApplicationNo. 2004/0156908 A1, paragraphs [0022], [0026]. Polaschegg furtherdescribes at paragraphs [0026] to [0027] a related observation, systemicanticoagulation in patients due to transfer of heparin locking solution.This observation has also been reported in medical journals, e.g., ascited in Polaschegg paragraph [0026].

Blood that enters the distal tip portion of the catheter by virtue ofbeing interchanged with locking solution quickly becomes stagnant andtherefore typically forms a clot inside the catheter near the distaltip, notwithstanding the presence of high-concentration heparin in thecatheter. In hemodialysis catheters and other catheters in the vascularsystem, the clot that forms in the distal tip portion is withdrawnduring conventional preparatory steps prior to initiating, for example,a hemodialysis session. These preparatory steps are the withdrawal ofthe lock solution, followed by a back flush with a small amount ofsaline to clear any residual blood or lock in the catheter. Thewithdrawn material (the lock solution, the clot and some blood) issucked into a syringe and is discarded.

However, efforts to withdraw the intra-luminal clot are not alwayseffective. Even in current practice, patency complications still occurat a relatively high rate even with high concentration heparin. Anyblood clot or clot fragment adhering to the luminal surface of acatheter increases blood flow resistance during treatment, especially atthe high blood flows typical of American hemodialysis. Establishedpractices in hemodialysis clinics set a maximum allowable flowresistance in the blood flow path, inferred from increased pressures anddecreased flow rates, that must not be exceeded as this may cause damageto red cells and may activate platelets, triggering a clotting response.Consequently, alarms are incorporated in hemodialysis machines to warnthe nurse when, e.g., pressure levels are exceeded. Corrective actionoptions are limited and mainly consist of slowing the blood flow rate orstopping the session and performing a catheter clot lysing procedure toopen up the catheters to restore patency. In either case, theinterventions are a major inconvenience to the patient and diminish theoperational efficiency of the hemodialysis clinic.

The trial results by Dr Allon were examined by researchers in a group ofexperiments at the Naval Blood Laboratory and Boston University MedicalSchool. These experiments determined that blood in contact with highconcentration taurolidine solution (such as occurs at the interfacebetween blood and taurolidine locking solution in a catheter) underwentchanges, including morphological changes to red cells that did nothappen with exposure to just heparin. However, the researchers were notable to determine exactly how their results were relevant to thefindings in the University of Alabama clinical trial.

Additional experiments were undertaken seeking to determinescientifically the reasons for the different results. This workcomprised in vitro experiments with modifications to thetaurolidine-based lock formulation. Testing was done with fresh humanblood using silicone rubber catheters commonly used in U.S. hemodialysispractice. Catheter lock and later blood test articles were subjected toconditions simulating as much as possible the environment that occurs inin vivo hemodialysis. Several catheters were tested simultaneously.

Test catheters were mounted in a vertical orientation and filled withvarious lock solution formulations. The distal tip was placed in abeaker containing fresh blood and blood was pulled into the catheter fora distance of about 3 centimeters. The distal tip and the proximal tipof each catheter were clamped shut. The distal portion of the catheterwas immersed in saline at ˜99° F. for 3 days. This time period wascomparable to the longest quiescent time period between livehemodialysis sessions. Test specimens included a conventional heparinlock, taurolidine based locks at various pH conditions, and taurolidinelocks with and without PVP additives.

The catheter contents were observed visually during the three day timeperiods. The catheters themselves were translucent and the materialholding the saline and the catheter allowed easy visual observation.

The first test sequence used the taurolidine lock in commercial use inEurope and a conventional heparin lock at 5,000 units per ml. It wasobserved that the high concentration heparin lock behaved verydifferently with respect to clotting compared to the taurolidineformulation. With respect to the heparin lock, clotting of the blood inthe catheter started on the end of the blood segment away from theblood-catheter lock interface. With the taurolidine based catheter lock,the blood started clotting right at the blood-catheter lock interface.In addition, the distal end clot was different in color. The clot formedwith the heparin lock was reddish brown, but the clot formed with thetaurolidine-based lock solution was black, suggesting the formation ofmet-hemoglobin. The presence of met-hemoglobin suggests damage to redblood cells by some agent.

Tests were also performed to simulate the procedure that occurs inpreparation for hemodialysis session. In a hemodialysis clinic, a nursewithdraws the lock solution from the catheter with a syringe and thecatheter is flushed with 10 ml of saline prior to the hook up to thehemodialysis machine. In the in vitro study referred to above. at theend of the 3 day quiescent period, a syringe was attached to theproximal end of the catheter and the clamp on the distal end wasremoved. The distal tip was then immersed in saline. A syringe was usedto withdraw the catheter contents.

It was noted that the clot in the heparin based locking solution couldbe easily removed intact from the catheter while the clot in thetaurolidine based experiments fragmented easily and crumbled. (One testin which the pH of the taurolidine-based locking solution was raised to6 resulted in less met-hemoglobin in the distal end clot but did notcompletely solve the problem.) The solidity and mechanical strength ofthe clots were qualitatively compared by compressing them with a smallrod. It was observed that the heparin clot was resilient and similar tothe behavior of soft rubber while the clot formed in thetaurolidine-based locking solution did not have any resiliency and brokeapart easily.

Also, in the catheters containing the taurolidine-based locking solutionthe procedure often did not completely remove the clot at the distalend. When the clot broke up, fragments remained adhered to the lumensurface of the catheter. Subsequently, in a like manner to the actualclinical situation, the catheter was flushed vigorously with a 10 mlsaline solution to determine if the clot fragment attachment could bebroken away. This flushing action did not usually dislodge the adheredfragments. In summary, the clot in the catheters containing the heparinlocking solution disengaged easily and completely, while the clot in thecatheters containing the taurolidine-based locking solution fragmented,with portions remaining stuck to the catheter lumen even after the flushprocedure.

These tests comparing the heparin locking solution with ataurolidine-based locking solution suggested that the potency problemsexperienced in the U.S. clinical trial at the University of Alabama wereexplained by difference in the nature of the clot formed at the distalend of the catheter with different locking solutions. During the NavalBlood Laboratory/Boston University Medical School experiments referredto above, it was determined that, with one exception, modifications ofthe taurolidine formulation did not affect the character of the distaltip clot. It was determined that the addition of very low concentrationsof heparin (final concentration about 100 units per ml) to thetaurolidine formulation minimized or eliminated the evidentlytaurolidine-induced changes to the character of the clots.

Based on this result, in vitro experiments were also undertaken with alow concentration of heparin added to a test specimen of the standardtaurolidine formulation. This solution formulation was also subjected tosimulated conditions during the simulated quiescent period. Theresulting observation was that the distal tip clot was able to becompletely removed intact just as if high concentrations of heparin hadbeen used and its mechanical properties and appearance were similar tothe high heparin concentration samples.

However, heparin is a dangerous substance demanding respect. It isusually given systemically to patients who are suffering dangerousdisorders involving clotting, such as acute thrombo-embolism. unstableangina, and active thombosis, which are life threatening or cause severeharm. Common complications of heparin administration are internalbleeding and heparin allergy, which can manifest in severe systemicclotting. In any patient, too high a level of heparin will causehemorrhaging. For hemodialysis patients, however, bleeding is a specialproblem, since many such patients have a reduced tendency to clot. It isan object of the current invention to provide a level of heparinaddition to taurolidine-based catheter lock solutions that willeliminate or minimize the danger that heparin infused into a patientwill prompt uncontrolled bleeding.

SUMMARY OF THE INVENTION

The present invention provides an improvement to Taurolidine basedantimicrobial and anti-coagulant lock solutions by reducing catheterpatency complications brought on by taurolidine reacting with red cellsand the characteristics of the clot formed in the distal portion of acatheter. The clot that forms in the presence of taurolidine has atendency to adhere to the inside surfaces of the hemodialysis catheterlumen and thereby produce high flow resistance which interferes with thehemodialysis treatment in some circumstances. These lock solutionscomprise pharmaceutically effective amounts or concentrations of: atleast one taurinamide derivative, at least one compound selected fromthe group consisting of biologically acceptable acids and biologicallyacceptable salts thereof, and heparin in small amounts andconcentrations insufficient by itself to provide protection of ahemodialysis catheter against loss of patency but sufficient to preventformation of clot fragments which adhere to the luminal surfaces of thehemodialysis catheter and resist removal.

In summary, investigators solved a problem that was first discoveredduring the commercialization of a new potent prophylactic which protectsagainst catheter infections. It was learned that under certaincircumstances, taurolidine and other taurinamide derivatives can reactwith blood, ultimately causing a patency complication in hemodialysiscatheters. Experiments were conducted both on the bench and in clinicaltrials to elucidate the nature of the problem and an unexpected solutionwas revealed, namely, adding low-concentration heparin to thetaurolidine formulation. Heparin is added in an amount too small toactually protect hemodialysis catheters from bulk clotting, but inamounts it was able to protect blood in a way that normal clottingprocesses did not produce clots with a tendency to stick to catheterwalls.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The most preferred embodiment of the invention is a combination of ataurolidine or taurultam based antibacterial solution in combinationwith an anticoagulant and/or calcium chelating substance such as citratealso in solution, the solution having a pH that maximizes theantimicrobial activity of the taurolidine, with a low concentration ofheparin, said concentration being so low that the threat of systemicanticoagulation of the patient is minimized or eliminated.

The therapeutic heparin concentration in the systemic circulation evenin patients with severe clotting tendencies rarely exceeds 1 unit/mlover the entire blood stream. More typically, concentrations aremaintained in the range of 0.2 units per ml of blood to 0.4 units per mlof blood.

Hemodialysis patients, on the other hand, more typically have lowplatelet counts and other blood deficiencies that inhibit clottingrather than promote it. Thus the upper limit for blood concentrationshould be conservative. The current invention assumes that 0.5 unitsheparin per ml of blood. in the total blood supply, is a safe upperlimit for prevention of adverse consequences from infusing heparin intoa patient's blood stream. However, the preferred upper limit would bebased on the minimum value typically cited for antithrombotic effect,namely the 0.2 units per ml of blood cited above.

Various means exist for estimating total blood volume for patients. Theinventor herein used the following formulas:

For men:

V _(B)=0.3669×(H)³+0.03219×W+0.604

For women:

V _(B)=0.3561×(H)³+0.03308×W+0.1833.

Where H is patient height in meters and W is patient total body weightin kilograms. The resulting blood volume is in liters (multiplied by1000 to obtain volume in ml). Using test values for typical patients, arange of blood volumes of 5000 to 6000 ml for males, 4000 to 5000 ml forfemales, is obtained. A mid-range value of 5000 ml is used in thecalculations that follow, but the wide variability from gender to genderand from patient to patient should be kept in mind.

A typical hemodialysis catheter volume is approximately 3 ml. Typicalunavoidable spillage of catheter lock solution into the patient is about⅓ of that value. or 1 ml. If the concentration of heparin in thecatheter lock solution is L_(concentration), loss of that much heparininto the patient would produce a vascular concentration of:

(L _(concentration))(Spilled catheter volume)=(bloodconcentration)×(blood volume)

-   -   (where, in the most routine case, spilled catheter volume=1 ml        and blood volume=5000 ml).        Using the safe upper limit set forth above (i.e., 0.5 units/ml)        and the typical blood volume of 5000 ml, the nominal upper limit        of 2500 units of heparin per ml in the catheter lock solution is        obtained.

However, four factors militate in favor of a lower limit. First, patientblood volumes range as low as 3500 ml. Second, sometimes a practitionerinadvertently pushes the entire catheter volume of catheter locksolution into a patient. Third, hemodialysis patients have, aspreviously noted, a tendency to insufficient clotting. Fourth, theminimum heparin concentration for therapeutic anti-thrombotic effect is0.2 units per ml in patients with a tendency to form clots. Accordingly,one preferred embodiment of the current invention carries an upper limitfor heparin concentration of 1750 units heparin per ml. Anotherpreferred embodiment carries an upper limit for heparin concentration of1000 units heparin per ml. A third preferred embodiment carries an upperlimit of 833 units heparin per ml. A fourth preferred embodiment has anupper limit of 583 units per ml. a highly preferred embodiment for theupper limit is 500 units per ml. Combining factors produces a mosthighly preferred embodiment of 150 units per ml. As will be appreciatedby one skilled in the art, various concentrations of heparin up to 2500units per ml can be safe for specific patients.

Some time after the tests referred to above were completed, anadditional test specimen comprising the taurolidine formulation with alow concentration heparin (final concentration of about 125 unitsheparin per ml) was evaluated clinically in Germany. Work was undertakenat Dr. Sodemann's clinics to evaluate the taurolidine formulationmodifications to determine if they might affect flow resistance. Themodifications to the taurolidine locking solution included an increasein the pH, the addition of PVP to taurolidine, and the incorporation ofminimal amounts of heparin (e.g., 125 units per ml) to the taurolidinebased catheter lock solution.

Dr Sodemann was not able to observe any difference regarding flowresistance or any other clinical parameter. However. this observationwas in the context that Dr. Sodemann had never seen a decrease incatheter patency using taurolidine-based locks as compared to highconcentration heparin-based locks in the first place.

Clinical testing was then performed in French clinics on patients whohad previously experienced flow resistance problems. In this group ofpatients it was observed that the addition of low concentration heparinreduced the need for flow resistance intervention, i.e., lysing, to lowrates, comparable to those experienced with high concentration heparinlock solutions.

Subsequently other patients who had patency complications in Finland andAustria were tested with the taurolidine plus citrate locking solutionwith low concentration heparin added. In these cases also. animprovement over the original taurolidine formulation was noted andachieved patency rates similar to the patency rates patients forpatients whose catheters were locked with high concentration heparinalone. In various experimental circumstances, concentrations of heparinas low as 50 units heparin per ml of catheter locking solution werefound to have the beneficial effect of the current invention.

The taurinamide derivatives referred to are antimicrobial compoundswhich have been chemically described in earlier applications referencedabove, which are incorporated by reference herein. The most preferredsubstance in this family is taurolidine. These compounds, condensationproducts of taurinamide and formaldehyde, are active not only againstboth gram-positive and gram-negative bacteria but also against exotoxinsand endotoxins. For the purposes of this application these compounds aregenerically and collectively referred to as taurolidine.

The concentration of taurolidine in such solutions is preferably in therange of from about 0.4 to about 5% by weight, depending upon thesolubility of the compound. Recent experiments have shown that additionof citrates and citric acid in combination, or alternatively theaddition of citric acid and adjustment of the pH with sodium hydroxide,such that the pH of the end solution is in the vicinity of 5.2 to 6.5,substantially increases the biocidal effectiveness of taurolidinesolution. The approach creates a buffer system of citric acid/sodiumcitrate by adjustment of pH using sodium hydroxide. This buffer systemalso resists changes in the pH due to the oxidation of formaldehyde toformic acid.

In addition, citric acid is a known antioxidant. Thus the use of citricacid and sodium citrate in this combination thus increases the stabilityand solubility of taurolidine in solution and prevents or severely slowsdown the precipitation out of solid taurolidine and reaction productsfrequently seen in taurolidine solution prepared with PVP. Long termstability tests have verified this result. The composition employed inthe practice of the present invention preferably also contains apharmacologically acceptable carrier solution, such as, water, Ringer'ssolution, or saline.

Other biologically acceptable acids and biologically acceptable saltsthereof are possible for combination with taurolidine. Other possiblesuch acids are acetic acid, dihydroacetic acid, benzoic acid, citricacid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleicacid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid,vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid,ethylenediaminetetraacetic acid (EDTA), ethyleneglycol-bis-{β-aminoethyl ether}-N,N,N′,N′-tetraacetic acid, anddiethylenetriamine pentaacetic acid, esters of p-hydroxybenzoic acid(Parabens), and the like, and biologically acceptable salts of theforegoing, such as, ammonium phosphate, potassium citrate, potassiummetaphosphate, sodium acetate, sodium citrate, sodium lactate, sodiumphosphate, and the like. A blood anticoagulating amount of an acidselected from the group consisting of citric acid, phosphoric acid,ethylenediaminetetraacetic acid (EDTA), ethyleneglycol-bis-{β-aminoethyl ether}-N,N,N′,N′-tetraacetic acid. anddiethylenetriamine pentaacetic acid and biologically acceptable saltsthereof is preferred. It is preferred that the acid employed in thepractice of the present invention he an organic acid. especially onehaving at least one carboxyl group, particularly citric acid or EDTA. Itis more preferred that the acid be citric acid and most preferred thatit be used in combination with a citrate salt, e.g., sodium citrate,since, in addition to its pH lowering and anticoagulation capabilities,it is also known to be an antiseptic at the 3% level.

Since calcium is one factor that is known to have a role in thecoagulation of blood, it is believed possible that at least part ofEDTA's efficacy in anticoagulant activity may be brought about by thismeans. Sodium citrate is also believed to have anticoagulationproperties by virtue of its ability to generate insoluble calciumcitrate.

The acid and/or salt will be used in a concentration effective to bringabout the desired volume anticoagulation effect and, at the same time,bring about, or help to bring about, an appropriate pH for biocidaleffect. Heparin is added in low concentrations, preferably 50 units perml to 150 units per ml. Typically, the combined antimicrobial, heparinand anticoagulant composition of the present invention will have a pH inthe range of from about 3.0 to about 7, preferably from about 3.5 toabout 6.5 and, most preferably from about 4.5 to about 6.5. Methods foradjusting the pH, familiar to those of skill in the art, can beemployed. Where, as is preferred, trisodium citrate and citric acid areemployed in the practice of the present invention, the trisodium citratewill typically be used in a concentration range of from about 5 to about50 grams per liter. The citric acid will then be added in sufficientamount to bring the pH to the desired level. The formulation which is apreferred embodiment comprises about 1.35% Taurolidine, 4% citrate andacidic pH, generally in the range of 5 to 6.

Although the process of the present invention is primarily andpreferably directed to maintaining the patency and asepsis of implantedhemodialysis catheters, beneficial effects may also be obtained inapplying the process to other, similar, devices, such as, central venouscatheters, peripheral intravenous catheters, arterial catheters,Swan-Ganz catheters, umbilical catheters, percutaneous non-tunneledsilicone catheters, cuffed tunneled central venous catheters as well aswith subcutaneous central venous ports.

Various features and aspects of the present invention are illustratedfurther in the examples that follow. While these examples are presentedto show one skilled in the art how to operate within the scope of theinvention, they are not intended in any way to serve as a limitationupon the scope of the invention.

1. A locking solution composition for treating and preventing infectionand flow reduction in blood catheters comprising a solution of: a. atleast one taurinamide derivative; b. a biologically acceptable acid anda biologically acceptable salt of said acid in a combination that bringsthe pH of the combination into a range that enhances antimicrobialactivity of the taurinamide derivative; and c. low concentrationheparin, wherein the heparin concentration is sufficient to preventreactions of the taurinamide derivative with stagnant blood but lowenough that expulsion and/or spillage of the solution into a patient'sbloodstream carries a low risk of patient hemorrhage.
 2. The compositionof claim 1 wherein the biologically acceptable acid is chosen from thegroup citric acid and lactic acid and the biologically acceptable saltis chosen from the group citrate and lactate.
 3. The composition ofclaim 1 wherein the taurinamide derivative is taurolidine, thebiologically acceptable acid is citric acid, the biologically acceptablesalt is citrate, and the pH range is 5.2 to 6.5.
 4. The composition ofclaim 3 wherein low concentration heparin is in the range of 50 to 2500units per ml.
 5. The composition of claim 4 wherein low concentrationheparin is in the range of 50 to 1750 units per ml.
 6. The compositionof claim 4 wherein low concentration heparin is in the range of 50 to500 units per ml.
 7. The composition of claim 4 wherein the lowconcentration heparin is in the range 50 to 150 units per ml.
 8. Amethod of enhancing the antimicrobial activity and resistance to flowreduction produced by a catheter locking solution comprising taurolidinein combination with citrate and citric acid by maintaining the pH in therange of 5.2 to 6.5 and of protecting a catheter against taurolidinereaction with blood therein by adding low concentration heparin.
 9. Themethod of claim 8 wherein low concentration heparin is in the range of50 to 2500 units per ml.
 10. The method of claim 8 in which the lowconcentration heparin is in the range of 50 units per ml to 1750 unitsper ml.
 11. The method of claim 8 in which the low concentration heparinis in the range of 50 units per ml to 500 units per ml.
 12. The methodof claim 8 in which the low concentration heparin is in the range of 50units per ml to 150 units per ml.
 13. A composition for treating andpreventing infection and patency loss in hemodialysis catheterscomprising a locking solution comprising: a. at least one taurinamidederivative; and b. low concentration heparin, wherein the heparinconcentration is sufficient to prevent reactions of the taurinamidederivative with stagnant blood but low enough that expulsion and/orspillage of the solution into a patient's bloodstream carries a low riskof patient hemorrhage.
 14. The composition of claim 13 wherein thetaurinamide derivative is taurolidine.
 15. The composition of claim 13wherein heparin is added in concentration in the range of 50 to 2500units per ml.
 16. The composition of claim 13 wherein low concentrationheparin is in the range of 50 to 1750 units per ml.
 17. The compositionof claim 13 wherein low concentration heparin is in the range of 50 to500 units per ml.
 18. The composition of claim 13 wherein the lowconcentration heparin is in the range 50 to 150 units per ml.
 19. Alocking solution composition for treating and preventing infection andflow reduction in catheters comprising a solution of: a. at least onetaurinamide derivative; b. a biologically acceptable acid in sufficientconcentration to bring the pH of the composition into a range thatenhances antimicrobial activity of the taurinamide derivative; and c.low concentration heparin, wherein the heparin concentration issufficient to prevent reactions of the taurinamide derivative but lowenough that expulsion and/or spillage of the solution into a patient'sbloodstream carries a low risk of patient hemorrhage.
 20. Thecomposition of claim 19 wherein the taurinamide derivative istaurolidine.
 21. The composition of claim 19 wherein heparin is added inconcentration in the range of 50 to 2500 units per ml.
 22. Thecomposition of claim 19 wherein low concentration heparin is in therange of 50 to 1750 units per ml.
 23. The composition of claim 19wherein the low concentration heparin is in the range 50 to 500 unitsper ml.
 24. The composition of claim 19 wherein the low concentrationheparin is in the range 50 to 150 units per ml.